6-Pyridyl benzodiazepines antidepressants

ABSTRACT

Pharmaceutical compositions comprising, in unit dosage form, from about 0.5 mg. to about 100 mg. of a compound of the formula: ##SPC1## 
     Where R, R.sub. 1, R 2  and R 3  is hydrogen, methyl or ethyl, and R 4  is hydrogen, fluorine, chlorine, bromine, --NO 2 , --CF 3 , or methylthio, inclusive; including the pharmacologically acceptable acid addition salts thereof, in association with a pharmaceutical carrier. The process is the administration of the above compositions to humans at a dose of from about 0.1 mg./kg./day to about 10 mg./kg./day for antidepressant therapy with minimal sedative side effects.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.180,111, filed Sept. 13, 1971, now U.S. Pat. No. 3,767,661.

BRIEF SUMMARY OF THE INVENTION

This invention is a therapeutic composition for treating humans andanimals comprising a benzodiazepine of the Formula I and including thepharmacologically acceptable acid addition salts thereof in combinationwith a pharmaceutical carrier and a method for treatment of conditionsrequiring anti-depressant therapy and minimal sedative side effects.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the Formula I can be prepared by methods disclosed incopending application Ser. No. 180,111, filed Sept. 13, 1971, andBritish Pat. No. 1,360,693.

The currently used benzodiazepines, e.g., valium and librium are usefulas sedatives, hypnotics and minor tranquilizers. The most common use isin the treatment of anxiety and tension, however the sedative sideeffects present a problem to those who work or operate machinery. Thecompounds of this invention surprisingly have antidepressant activity, autility not found in the benzodiazepine class of drugs and does not havethe sedative side effects. Antidepressant drugs are agents that dostimulate and increase alertness of the central nervous system andelevate the mood of the depressed patient. The antidepressants act on avariety of depressive symptoms and syndromes in patients who areretarded or withdrawn. They aggravate symptoms of patients who areanxious, restless or suffering from insomnia. These patients are treatedwith a tranquilizer or sedative drugs. The tranquilizer produce acalmness or relaxation and have a mild sedative effect. Sedatives inducea modest functional depression of CNS activity resulting in quiescence.

The compounds of the Formula I unexpectedly show only antidepressiveactivity and minimal antianxiety. They can be used when prepared in unitdosage forms, in association with a pharmaceutical carrier for treatmentof depression.

The compositions of the present invention are presented for systemicadministration to humans and animals in unit dosage form and can beadministered orally, parenterally, and rectally.

For oral administration either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof Formula I is mixed with conventional ingredients such as talc,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Wafers are prepared in the same manner as tablets, differing only inshape and the inclusion of sucrose or other sweetener and flavor. Intheir simplest embodiment, capsules, like tablets, are prepared bymixing the compound with an inert pharmaceutical diluent and filling themixture into a hard gelatin capsule of appropriate size. Soft gelatincapsules are prepared by machine encapsulation of a slurry of thecompound with an acceptable vegetable oil, light liquid petrolatum orother inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs,and suspensions can be prepared. The water-soluble forms can bedissolved in an aqueous vehicle together with sugar, aromatic flavoringagents and preservatives to form a syrup. An elixir is prepared by usinga hydro-alcoholic (ethanol) vehicle with suitable sweeteners such assugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with a syrup vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampul and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use. Parenteral suspensionsare prepared in substantially the same manner except that the compoundis suspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

For rectal administration a compound of the Formula I in the form of asuppository is preferred and is prepared by compounding with a solidwhich melts at body temperature, e.g., cocoa butter or a solid which ismiscible in body fluids, e.g., polyethylene glycol.

The term unit dosage form as used in the specification and claims refersto physically discrete units suitable as unitary dosages for humansubjects and animals, each unit containing a predetermined quantity ofactive material calculated to overcome depression in association withthe required pharmaceutical diluent, carrier, or vehicle. Thespecifications for the novel unit dosage forms of this invention aredictated by and directly dependent on (a) the unique characteristics ofthe active material and the particular effect to be achieved, and (b)the limitations inherent in the art of compounding such an activematerial for use in humans and animals, as disclosed in detail in thisspecification, these being features of the present invention. Examplesof suitable unit dosage forms in accord with this invention are tablets,capsules, pills, suppositories, powder packets, granules, wafers,cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampuls, vials,segregated multiples of any of the foregoing, and other forms as hereindescribed.

The dosage of the compound for treatment depends on route ofadministration, the age, weight, and condition of the patient. Thedosage to be administered is calculated on the basis of from about 0.1to about 10 mg./kg. weight of subject/day.

The compound is compounded with a suitable pharmaceutical carrier inunit dosage form for convenient and effective administration. In thepreferred embodiments of this invention, the dosage units contain thecompound in: 0.5, 1, 10, 25, 50, 250 and 500 mg. amounts for systemictreatment; and 0.5% to 25% w/v for parenteral treatment.

The following examples are illustrative of the best mode contemplated bythe inventor for carrying out his invention and are not to be construedas limiting.

EXAMPLE 1

A lot of 10,000 tablets, each containing 0.5 mg. of8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineis prepared from the following types and amounts of ingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine                   5 gm.                                               Dicalcium phosphate       1,500 gm.                                           Methylcellulose, U.S.P. (15 cps.)                                                                       60 gm.                                              Talc                      100 gm.                                             Lactose                   50 gm.                                              Corn Starch               200 gm.                                             Calcium stearate          12 gm.                                          

The benzodiazepine and dicalcium phosphate are mixed well, granulatedwith 7.5 percent solution of methylcellulose in water, passed through aNo. 8 screen and dried carefully. The dried granules are passed througha No. 12 screen, mixed thoroughly with the talc, lactose, starch andstearate, and compressed into tablets.

These tablets are useful for treatment of depression at a dose of 2-4tablets a day.

EXAMPLE 2

One thousand two-piece hard gelatin capsules, each containing 1 mg. of8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineare prepared from the following types and amounts of ingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine                  1       gm.                                          Lactose                  100     gm.                                          Talc                     25      gm.                                          Magnesium stearate       2.5     gm.                                          Starch                   150     gm.                                      

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful for treatment of depression at a dose of1 capsule four times a day.

EXAMPLE 3

One thousand tablets for sublingual use are prepared from the followingingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine                   10 gm.                                              Polyethylene glycol, 4000                                                     powdered                 150 gm.                                              Polyethylene glycol, 6,000                                                    powdered                  75 gm.                                          

The ingredients are mixed well and compressed into sublingual-typetablets weighing 235 mg.

These tablets placed under the tongue are useful in the rapid inductionof treatment for depression at a dose of 1 tablet 4 times a day.

EXAMPLE 4

Soft gelatin capsules for oral use, each containing 10 mg. of8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineare prepared by first dispersing the micronized compound in corn oil torender the material capsulatable and then encapsulating in the usualmanner.

One capsule taken daily is useful for depression.

EXAMPLE 5

One thousand tablets, each containing 25 mg. of8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineare made from the following types and amounts of ingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine                   25 gm.                                              Lactose                  355 gm.                                              Microcrystalline cellulose NF                                                                          100 gm.                                              Starch                    16 gm.                                              Magnesium stearate powder                                                                               4 gm.                                           

The ingredients are screened and blended together and pressed into 500mg. tablets.

The tablets are useful for treating depression at a dose of 1 tablet 3times a day.

EXAMPLE 6

A sterile preparation suitable for intramuscular injection andcontaining 10 mg. of8-chloro-1-[2-(dimethylamino)-ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinein each milliliter is prepared from the following ingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-5-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine                 10        gm.                                         Benzyl benzoate         2         ml.                                         Methylparaben           1.5       gm.                                         Propylparaben           0.5       gm.                                         Cottonseed oil q.s.     1,000     ml.                                     

One milliliter of this sterile preparation is injected for treatment ofneurotic depression.

EXAMPLE 7

One thousand tablets, each containing 50 mg. of8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinemethanesulfonate are made from the following types and amounts ofingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine methanesulfonate  50 gm.                                              Lactose                  330 gm.                                              Microcrystalline cellulose NF                                                                          100 gm.                                              Starch                    16 gm.                                              Magnesium stearate powder                                                                               4 gm.                                           

The ingredients are screened and blended together and pressed into 500mg. tablets.

The tablets are useful for treating neurotic depression at a dose of 1tablet 3 times a day.

EXAMPLE 8

One thousand two-piece hard gelatin capsules, each containing 100 mg. of8-chloro-1-[2-(dimethylamino)-ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineare prepared from the following types and amounts of ingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine                  100     gm.                                          Talc                     25      gm.                                          Lactose                  150     gm.                                          Magnesium stearate       2.50    gm.                                          Gelatin                  100     gm.                                      

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful to reduce depression in adults at a doseof one to three capsules daily.

EXAMPLE 9

A sterile aqueous solution for parenteral administration containing 25mg. of8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinemethanesulfonate in each 1 ml., is prepared from the following types andamounts of ingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine methanesulfonate  25 gm.                                              Water for injection q.s. 1000 ml.                                         

The active ingredient is dissolved in the water for injection and thesolution sterilized by filtration. The sterile solution is filled into 1ml. sterile vials and sealed.

The composition is useful for treating depression at a dose of 1 to 2ml. daily.

EXAMPLE 10

One thousand ml. of an elixir, containing 100 mg. of8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinemethanesulfonate in each 5 ml. is prepared from the following types andamounts of ingredients:

    8-chloro-1-[2-(dimethylamino)-                                                ethyl]-6-(2-pyridyl)-4H-s-                                                    triazolo[4,3-a][1,4]benzodi-                                                  azepine methanesulfonate                                                                              20        gm.                                         Citric acid             0.1       gm.                                         F.D.C. Red No. 1        0.04      gm.                                         Saccharin               0.1       gm.                                         Sucrose                 200.0     gm.                                         Oil in spearmint        0.1       gm.                                         Oil in wintergreen      0.1       gm.                                         Polysorbate 80 U.S.P.   1.0       gm.                                         Ethanol 95%             200.0     ml.                                         Glycerin                150.0     ml.                                         Water q.s.              1,000.0   ml.                                     

The sugar is dissolved in 450 ml. of water and the citric acid, colorand the8-chloro-1-[2-(dimethylamino)-ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine methanesulfonate added thereto. The saccharinis added to the mixture of alcohol and glycerin and stirred untildissolved. The flavors are mixed with the polysorbate 80 and added tothe alcohol-glycerin solution followed by the addition of the sugarsolution and sufficient water to make 1,000 ml.

The elixir is useful in the treatment of depression at a dose of 1 to 2teaspoons a day.

EXAMPLE 11

Following the procedure of the preceding Examples 1 through 8,inclusive, unit dosage forms are similarly prepared substituting anequal amount each of8-chloro-1-[2-aminoethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-chloro-1-[2-(methylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-chloro-1-[2-(ethylmethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-chloro-1-[2-(diethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-bromo-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-bromo-1-[2-(methylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-trifluoromethyl-1-[2-(amino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-bromo-1-[2-(diethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-bromo-1-[2-(ethylmethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-fluoro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-fluoro-1-(2-aminoethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-nitro-1-[2-(methylamino)ethyl]-6-(2-pyridyl)4H-s-triazolo-[4,3-a][1,4]benzodiazepine,8-nitro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-(methylthio)-1-(2-aminoethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-chloro-1-[2-(aminopropyl)]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-chloro-1-[2-(methylamino)propyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-chloro-1-[2-(diethylamino)propyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-bromo-1-[2-(dimethylamino)butyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-nitro-1-[2-(dimethylamino)butyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-fluoro-1-[2-(dimethylamino)propyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-methylthio-1-[2-(dimethylamino)propyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-chloro-1-[2-(dimethylamino)butyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,8-methylthio-1-[2-(dimethylamino)-propyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinefor the8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

I claim:
 1. A process for treating depression comprising theadministration to a human or animal subject an effective antidepressantamount of a compound of the formula: ##SPC2##wherein R, R₁, R₂ and R₃are hydrogen, methyl or ethyl, and R₄ is hydrogen, fluorine, chlorine,bromine, --NO₂, --CF₃, or methylthio, inclusive; or a pharmacologicallyacceptable acid addition salt thereof, in association with apharmaceutical carrier.
 2. The process of claim 1 wherein from about 0.1mg./kg./day to about 1 mg./kg./day of the compound is administered. 3.The process of claim 2 wherein the compound is8-chloro-1-[2-(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.4. The process of claim 2 wherein the compound is8-fluoro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.5. The process of claim 2 wherein the compound is8-chloro-1-[2-(dimethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinemethanesulfonate.
 6. The process of claim 2 wherein the compound is8-chloro-1-(aminoethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.7. The process of claim 2 wherein the compound is8-chloro-1-[2-(methylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.8. The process of claim 2 wherein the compound is8-trifluoromethyl-1-[2-(dimethylamino)-methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.9. The process of claim 2 wherein the compound is8-nitro-1-[2-(dimethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.